The global AIDS epidemic continues to rage, with 40 million people infected with HIV-1 or debilitated by AIDS. Analysis of HIV-1 infected individuals and studies in animal models show the rapid onset of AIDS requires expression of the HIV-1 protein Nef. This lentivirus protein has manifold roles in the pathophysiology of AIDS, including the downregulation of the host CD4 and MHC-1 molecules in infected cells. The downregulation of CD4 eliminates interference of the viral receptor with HIV-1 envelopment and MHC-1 downregulation enables the virus to evade the immune surveillance system. Despite the importance of Nef-mediated downregulation of MHC-1 to the development of AIDS, little is known regarding the cellular and biochemical pathways that control this process. Recently, this laboratory reported the identification of the cellular protein, PACS-1, that they believe controls the Nef-mediated downregulation of MHC-1. They showed PACS-1 binds to HIV-1 Nef to form a protein complex in cells. Moreover, HIV-1 Nef requires PACS-1 to specifically downregulate MHC-1 by redistributing this immune surveillance molecule to the trans-Golgi network. The identification of the PACS-1/Nef complex has provided some of the first insights into the mechanism of HIV-1-mediated downregulation of MHC-1 molecules. The proposed studies first will identify the structural determinants required for the association of HIV-1 Nef and PACS-1 and elucidate how formation of the PACS-1/Nef complex is regulated. Second, they will identify the cellular pathway used by PACS-1/Nef to sequester MHC-1 in the trans-Golgi network. Third, they will test the possibility that the PACS-1/Nef complex is a potential pharmacological target for disrupting HIV-1 immune evasion. Together, these studies will increase our knowledge of the biochemical and cellular basis of HIV-1's ability to evade the immune surveillance system, as well as provide new insights into pharmacological strategies to block this process.